Cardiovascular disease represents a major cause of death worldwide. Despite the advances in the treatment of Acute Myocardial Infarction (AMI) and Heart Failure (HF) over the past several decades, these diseases are the most significant for health in the U.S. According to the 2009 heart disease and stroke statistics as part of the American Heart Association (AHA) statistical update, it is estimated that 1 out of every 5 deaths in the United States is caused by coronary artery heart disease.
Although numerous interventions have been studied over the past 50 years to limit infarct size in patients presenting with MI, almost none have made it to the clinics. A major reason is that almost all of these therapies require administering the agent before the ischemic episode, which is impractical in patients coming to the hospital with MI. Many of the adjunctive therapies along with reperfusion therapy have failed in clinical trials.
More than 900,000 Americans suffer a myocardial infarction each year, one-third of these are diagnosed as acute ST-segment elevation myocardial Infarction (STEMI), and the 30-day mortality rate from this disease is about 30%. Thus, there is a need for novel therapeutic agents capable of minimizing or preventing damage to the human myocardium during ischemic episodes.
Presently, approximately 5.1 million people in the United States suffer from HF. In 2009, one in nine deaths listed HF as a contributing cause. Furthermore, of those who develop HF, approximately half will die within 5 years. Finally, the annual cost of HF care to the healthcare system is estimated at $32 billion dollars. Thus, there is a need for novel therapeutic agents capable of minimizing or preventing development of or advancement of HF.
β-Adrenergic signaling is a key process in cardiovascular, central nervous system and metabolic regulation. Unfortunately, the prolonged use of β-agonists and β-antagonists is plagued by poor tissue selectivity, sensitization and desensitization following therapy, and dynamic changes to the β-adrenergic receptors that are inconsistent among disease states. Through β-adrenergic signaling, adenylyl cyclases are activated.
The adenylyl cyclases (ACs) are a family of enzymes that are key elements of signal transduction by virtue of their ability to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP is a key regulator of PKA leading to calcium signaling in the human myocardium. At least nine isoforms of adenylyl cyclase are known and unique isoform combinations are expressed in a tissue specific manner. Type V AC is the predominant isoform found in heart tissue. Thus, the development of isoform specific inhibitors of adenylyl cyclase is a useful strategy toward the design of novel therapeutic agents targeting cardiac function.